Pathophysiology of SARS- Coronavirus- 2 in mild to severe cases

                           

electron microscope view of SARS COV-2attacking lung cells 

Introduction:

The SARS coronavirus 2 comes from the subfamily Orthocoronavirinae, in the family Coronaviridae. These viruses occur in many organisms including humans and have been associated with zoonotic diseases for a long time. These positive-sense RNA viruses are commonly known to cause common cold in humans and rarely diarrheal symptoms in children. The cases that these viruses have started to affect humans are recent. Being completely new viruses for causing human diseases they have been a pretty nuisance in the past few decades. The 2003 SARS outbreak, 2013 MERS outbreak, and recent 2019 SARS COVID-19 outbreak are the periods when these viruses appeared so aggressively to cause Pandemic. The occurrence of  SARS and MERS was not that widespread and was contained within those fixed geographical locations but the case is not the same in SARS-COVID-2 where the whole world is suffering from a huge pandemic worldwide spreading of the virus and increasing fatalities.

Knowing about the virus:

The SARS- COV-2 is a positive-sense single-stranded RNA virus that is spherical in shape with spike proteins adjusted like a crown thus given the name coronavirus.

 

The proteins that appear in the form of corona are:

1. Spike proteins

2. Hemaglutinesterase protein

3. M protein 

4. Envelope protein 

The outer covering of the virus is made up of phospholipids derived from the cell wall of an organism called the envelope.

 

The innermost covering is a protein that protects the genetic material inside called the capsid.

Inner nuclear material:

It is a positive-sense single-stranded RNA. 

 

Similarity of the virus nuclear material:

The nuclear material has been found 96.2% similar to the bat coronavirus Ra-Tg-13

The intermediate host of the virus is believed to be Pangolin where the virus amplifies and goes on homologous recombination to suit for infecting the humans.

Subtypes:

S type- common in 30% of people, less aggressive, has a zoonotic connection

L type- common in 70% of people, more aggressive and severe, believed to have been evolved 

Epidemiology:

Case fatality rate: 4 to 5 %

 Basic reproduction rate (Ro): 2 to 3 

Series of interval (Si): 4 days

 Rate of transmission: Ro+Si = around 6 to 7

Incubation period: Average about 5 to 6 days and maybe up to 14 days 

Mode of transmission: via respiratory droplets, can be aerosolized for up to 3 hours, and also can be transmitted via fomites, might also be transmitted via the faecal-oral route,  vertical transmission might be possible but research must be done 

How long can coronavirus survive in the surfaces:

Aluminium, latex and copper: 8 hours  

Cardboard: 24 hours

Plastics, stainless steel: 3 days 

Wood and glass: 5 days

Pathophysiology of the virus:

Target cells: Type 2 pneumocytes in the lungs alveoli 

                           blood air barrier  

Mechanism of attachment and endocytosis:

The virus binds on ACE-2 receptors by the help of spike proteins and hemaglutinesterase protein  (Also some speculate that the virus bind to TMPRSS2 receptor protein in the cell surface). After binding to the receptors, endocytosis is facilitated by the cell which engulfs the virus particle in the form of endosome.

The endosome fuses with the lysosomes where the viral capsid is digested by the proteases and finally the positive-sense single- stranded RNA is released in the cytosol.

SSRNA binds with the ribosomes in the rough endopla

smic reticulum.

This initiates the translation of proteins called polyproteins which are essentially the combination of viral protein particles.

These polyproteins are cleaved by the proteases to form fundamental viral proteins listed above.

Along with the formation of these polyproteins the Ribosomes also translate RNA dependent RNA polymerase which further multiplies viral particles.

RNA dependent RNA polymerase:

This protein is responsible for multiplying viral particles by forming more viral RNA. It has two sides one of which forms negative sense single stranded RNA and another side which converts that -ve SSRNA into +ve SSRNA.

These above processes repeat again and again forming mani RNA as well as proteins

RNAs and Proteins are eventually packaged by the Golgi apparatus and converted into exocytotic vesicles inside which they are reassembled into new viral particles.

Finally, the lipid bilayer of the vesicle fuses with the cell membrane releasing  viruses out of the cell. 

These above processes eventually fatigue the cell and causes cellular death of type 2 pneumocytes.

(Note: ACE-2 receptor is believed to downregulate the production of angiotensin-1 to angiotensin-2 which causes increase in angiotensin 2 causing acute lung injury)

What happens after cellular death and eventual cytokine storm:

Death of these pneumocytes causes releasing of signaling molecules including alpha interferon and beta interferon which eventually cause the nearby alveolar cells to release antiviral peptides to break down the viral particles, these cause the body to be prepared for the viral attack.

The cells also release damage-associated molecular patterns (DAMP's) and inflammatory cytokines which alerts the alveolar macrophages.

Activated alveolar macrophages release inflammatory mediators which include:
IL-1

IL-6

IL-8

TNF- alpha

gamma- interferon

These inflammatory cytokines have multiple actions to cause adverse pathological conditions when released in large amounts which is called cytokine storm. The effects that they cause are as follows:

1. These molecules move out in the pulmonary capillary area which increases vascular permeability. This in result causes leakage of fluid in interstitial space in between pulmonary capillary and alveoli resulting in pulmonary edema.                                                                                                                                                                                                                                                                                                                   
2. The fluid in interstitial space accumulated due to increased vascular permeability moves to alveolar space causing alveolar edema.                                                                                                                                                                                                                             
3. Over time due to the ineffective diffusion of oxygen and carbon dioxide in and out from the body, lungs are unable to breathe effectively and chest muscles get fatigued. As a result, carbon dioxide is unable to diffuse out to the atmosphere resulting in increased pCO2. This is called hypercapnia. Hypercapnia results in respiratory acidosis due to increased carbonic acid formation.                                                                                                                                                                                                                                      
4. Cytokines also act on the vascular endothelium and activate proteins called VCAM's (vascular cell adhesion molecules) and increase their expression. Their main role is that they attach WBC's and helps in pulling them to alveoli. These WBc's include neutrophils and macrophages which will perpetuate the inflammatory response.                                                                                                                                                                     
5. These cytokines, more importantly, IL-8 also activates neutrophils as further immune response, these neutrophils release reactive oxygen species and proteases which in turn destroy all the cells and surrounding parenchyma.                                                                                                                                                                                                                             
6. Type 2 pneumocytes release surfactant which decreases the surface tension of lungs, but after they get destroyed, surface tension increases resulting in alveolar collapse and progressing to hypoxemia and shortness of breath.                                                                                                                                                                                                                         
7. Also, the decrease in type 1 pneumocytes results in decreased diffusion of air into the blood which results in hypoxemia and shortness of breath.                                                                                                                                                   

Newer researches also have found that this cytokine storm can increase the activity of the procoagulants and decrease anticoagulant activity, this can result in the formation of blood clots in pulmonary endothelial walls which can potentially progress to pulmonary embolism.

Cough reflex:

Damage suffered by these pneumocytes results in the release of more cytokines, prostaglandins, and leukotrienes, these leukotrienes stimulate the receptors of the vagus nerve which sends the impulse to the cough center in medulla causing cough reflex.

Types of cough:

Dry cough: 70% of cases

Wet or productive cough: 30% of cases

(Note: Leukotrienes also cause bronchoconstriction which further prevents gaseous exchange resulting in hypoxemia)

 

Fever:

The surge in IL-1 and TNF- alpha leads to stimulation of hypothalamus which results in increased secretion of prostaglandin E2 which cause increase in body's thermostat causing fever.

Systemic Inflammatory Response Syndrome(SIRS):

These all inflammatory response in the lungs due to cytokines storm might also spread on the systemic circulation leading to systemic inflammatory response syndrome (SIRS).

Disseminated intravascular coagulation:

The increase in procoagulant as a result of cytokine storms and might cause multiple clots in the vessels consuming up all the coagulatory proteins in the blood. As result blood is unable to clot when required, this is called disseminated intravascular coagulation.

Multiple organs failure:

Multiple clots formed all over the body can reduce the perfusion to the vital organs resulting in hypoxia, coagulation necrosis, ischemia, and finally organ failure.

Asymptomatic patients:

The ACE receptors are also present in the nasal mucosa and the tongue, they are also present in pharyngeal mucosal cells thus the asymptomatic person may experience:

Agausia- lack of taste 

Anosmia- lack of smell

Laryngitis or sore throat

Systemic Manifestations:

Pulmonary manifestations:

• Viral pneumonia
• Acute respiratory distress syndrome(ARDS)
• Pulmonary embolism
• Systemic inflammatory response syndrome(SIRS)
• Multi-organ system failure(MSOF)

Cardiac manifestations:

• Cardiac failure due to SIRS
• Cardiomyopathy due to decreased cardiac function

Renal manifestations: the presence of ACE2 receptors

• Decrease in renal function
• Anuria
• Dysuria
• oliguria

Gastro-intestinal manifestations:

• Abdominal pain
• Nausea 
• Vomiting 
• Diarrhea

Sources: Wikipedia, WHO, Youtube, Robbins and  Cortans pathological basis of disease, Ninja nerd science youtube channel, Najeeb video lectures, spillover by David Quemann